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Nerve Regeneration: Everyone does it, but you

Dogs do it, frogs do it, and even whales do it! No, this isn’t everyone poops. I’m talking about regrowing nerves after an injury and sadly, we don’t do it… yet. Now, thanks to a small molecule that may be able to convince damaged nerves to not just grow, but effectively rewire circuits, that all could change. Such breakthrough could eventually lead to therapies for the thousands of Americans with severe spinal cord injuries and paralysis.

“This research implies that we might be able to mimic neuronal repair processes that occur naturally in lower animals, which would be very exciting,” says the study’s senior author and Salk professor Kuo-Fen Lee.

For a damaged nerve to regain function, its long, signal-transmitting extensions [known as axons] need to grow and establish new connections to other cells.

In a previous study published last summer, the team found that the protein p45 promotes nerve regeneration by preventing the axon sheath [a fatty insulating tissue known as  myelin] from inhibiting regrowth. However, humans, primates and some other more advanced vertebrates don’t have p45. Instead, the researchers discovered a different protein, p75, that binds to the axon’s myelin when nerve damage occurs in these animals. Instead of promoting nerve regeneration, p75 actually halts growth in damaged nerves, a counterintuitive evolutionary step for sure.

“We don’t know why this nerve regeneration doesn’t occur in humans. We can speculate that the brain has so many neural connections that this regeneration is not absolutely necessary,” Lee says.

Using that information, the new study, the scientists looked at how two p75 proteins bind together and form a pair that latches onto the inhibitors released from damaged myelin.

By studying the configurations of the proteins in solutions using nuclear magnetic resonance [ since we shorten everything NMR] technology, the researchers found that the growth-promoting p45 could disrupt the p75 pairing.

“For reasons that are not understood, when p45 comes in, it breaks the pair apart,” says Lee, holder of the Helen McLoraine Chair in Molecular Neurobiology.

What’s more, the p45 protein was able to bind to the specific region in the p75 protein that is critical for the formation of the p75 pair, thus decreasing the amount of p75 pairs that bond to inhibitors release from myelin. With less p75 pairs available to bond to inhibitor signals, axons were able to regrow.

The findings suggest that there may be a way  — either using p45 or another disrupting molecule — that can effectively break the p75 pair. This could offer a possible therapy for spinal cord damage in the future. While there are several ways to go about this, one method of therapy could be to introduce more p45 protein to injured neurons. But a smarter tactic might be to introduce a small molecule that jams the link between the two p75 proteins.

“Such an agent could possibly get through the blood-brain barrier and to the site of spinal cord injuries,” Lee says.

So what’s next? Well researchers want to see if introducing p45 helps regenerate damaged human nerves.

“That is what we hope to do in the future,” Lee says.

The field of tissue regeneration is amazing and this step in nerve regeneration would be incredible. It’s amazing to think that I might be able to see that, not only in my lifetime, but soon! It’s things like this, baby steps toward something incredible that drives my passion with science. I can’t wait to see what the team has in store next and what other breakthroughs will come next!

Want more? Then you probably want the full study, which can be found —here!

Vilar M, Sung TC, Chen Z, García-Carpio I, Fernandez EM, Xu J, Riek R, & Lee KF (2014). Heterodimerization of p45-p75 Modulates p75 Signaling: Structural Basis and Mechanism of Action. PLoS biology, 12 (8) PMID: 25093680

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